News and commentary on what we consider to be the top new schizophrenia research developments most relevant for families, care takers and people who have schizophrenia. Hosted by Farzin Irani (PHD candidate), and Jacob Ballon, (MD candidate).

Lamotrigine (Lamictal) is an anticonvulsant medication (meaning it was originally created to help control seizures) that has been shown to have benefit in patients with bipolar disorder. It has an indication for the long term mood stabilization in bipolar disorder, and has been shown to have a slight anti-depressant effect in bipolar patients who are more prone to periods of depression. Small studies with lamotrigine used to augment clozapine (Clozaril) have shown some improvement in BPRS (Brief Psychotic Rating Scale) scores which indicates a decrease level of symptoms. In one study, symptoms were decreased by up to 75% in chronic treatment-resistant patients. In another study, Lamotrigine works primarily by blocking the neurotransmitter glutamate. Neurotransmitters are the chemicals in the brain that signal brain cells (neurons) to fire and do their job. All antipsychotics work, at varying levels of potency, by blocking the neurotransmitter dopamine. This led to the theory that schizophrenia must be caused in large part by an overabundance of dopamine related activity. However, recent studies have implicated the role of glutamate as also potentially being involved in the problems with schizophrenia.

In the first study, the authors utilized a “crossover” design to try and ascertain the effect of adding lamotrigine to clozapine in severe, treatment-resistant patients that were institutionalized in Finland. The crossover design means that subjects are assigned randomly to either receive a placebo or the active drug for the first half of the study and then are switched halfway through to receive the other. Neither the patient nor the researcher knows which part of the study the patient is on until the end of the trial when the schedule can be revealed. This design is helpful because it allows for patients to be compared with themselves minimizing the risk of bias that can be caused by differences between groups. The authors found that at the end of the study, there was a slight improvement in patients who took the lamotrigine. However, this was an average improvement that while statistically significant, is not very clinically meaningful. In other words, the benefit is measurable in a research setting, but is of overall very little meaning in the outside world. However, they noted that in 20% of the people, when they were on the labotrigine, they showed a very significant benefit (Decrease in the PANSS or Positive and Negative Symptoms in Schizophrenia Scale of 3 points) and in the other 80% of the time, the benefit was negligible. In a population of people who have not responded to medication in the past, improvements in 20% is a meaningful number in terms of benefit to the public.

In the second study, the authors wanted to look at lamotrigine in addition to other antipsychotics besides clozapine. They included patients with severe, treatment-resistant schizophrenia but who were taking antipsychotics other than clozapine. They assigned subjects randomly to either receive a placebo (dummy pill) or to receive lamotrigine at a slowly escalating dose up to 400mg per day (a typical maximum dose.) They assessed the patients after ten weeks and found that among patients that completed the study, those who received the lamotrigine had an improved symptom profile. Generally, it is considered to be a more rigorous research standard to consider all patients enrolled in a study, even if they don’t complete the study, as the reasons for a patient to discontinue the study may be related to a problem with the study medication and therefore should be considered a negative outcome unless there is a specific reason not to believe so. When the authors did that kind of analysis, they found that there was no statistically significant difference between the groups. This does not mean that the medication did not work; rather it implies that further research needs to be done to fully understand the effect.

Based on these data, it may be helpful to add lamotrigine to a patient’s drug regimen if they are not achieving therapeutic success with more conventional treatments. It is a reasonable choice to try as many patients did benefit however there were also several that did not. Research gives answers for overall populations however, and does not necessarily indicate if something will work or not work for a unique individual. There are risks to lamotrigine, not the least of which is a serious and potentially fatal skin rash called Stevens-Johnson syndrome, so the medication must be started and stopped slowly and carefully under guidance from a physician.

Funding notes:
1. The study was supported by funding from Annual EVO Financing (Special government subsidies). No support was provided by any pharmaceutical company.
2. This research was supported by a grant from the National Institute for Psychobiology in Israel (IK, UH-L). DJC and UH-L served as consultants at the GlaxoSmithKline Advisory Meeting on lamotrigine use in schizophrenia held at the American College of Neuropsychopharmacology 42nd Annual Meeting, December 7–11, 2003, San Juan, Puerto Rico.